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The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans
Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842765/ https://www.ncbi.nlm.nih.gov/pubmed/36646719 http://dx.doi.org/10.1038/s41467-023-35899-1 |
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author | Wu, Nan Ma, Yi-Cheng Gong, Xin-Qian Zhao, Pei-Ji Jia, Yong-Jian Zhao, Qiu Duan, Jia-Hong Zou, Cheng-Gang |
author_facet | Wu, Nan Ma, Yi-Cheng Gong, Xin-Qian Zhao, Pei-Ji Jia, Yong-Jian Zhao, Qiu Duan, Jia-Hong Zou, Cheng-Gang |
author_sort | Wu, Nan |
collection | PubMed |
description | Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD(+) via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H(2)O(2) formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H(2)O(2)-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD(+)-SIRT1 signaling and peroxisomal function. |
format | Online Article Text |
id | pubmed-9842765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98427652023-01-18 The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans Wu, Nan Ma, Yi-Cheng Gong, Xin-Qian Zhao, Pei-Ji Jia, Yong-Jian Zhao, Qiu Duan, Jia-Hong Zou, Cheng-Gang Nat Commun Article Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD(+) via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H(2)O(2) formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H(2)O(2)-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD(+)-SIRT1 signaling and peroxisomal function. Nature Publishing Group UK 2023-01-16 /pmc/articles/PMC9842765/ /pubmed/36646719 http://dx.doi.org/10.1038/s41467-023-35899-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wu, Nan Ma, Yi-Cheng Gong, Xin-Qian Zhao, Pei-Ji Jia, Yong-Jian Zhao, Qiu Duan, Jia-Hong Zou, Cheng-Gang The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans |
title | The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans |
title_full | The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans |
title_fullStr | The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans |
title_full_unstemmed | The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans |
title_short | The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans |
title_sort | metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in c. elegans |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842765/ https://www.ncbi.nlm.nih.gov/pubmed/36646719 http://dx.doi.org/10.1038/s41467-023-35899-1 |
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